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Screening for molecular glues - Challenges and opportunities.

Geoffrey A Holdgate1, Catherine Bardelle2, Sophia K Berry2

  • 1Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park, UK.

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|December 17, 2023
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Summary

Molecular glues are small molecules that stabilize protein interactions, often enhancing target-E3 ligase binding for therapeutic effects. This review covers induced proximity, identification methods, and screening approaches for molecular glues.

Keywords:
CompetitionDegradationMolecular glueProtein proximityStabilisationUbiquitinationUndruggable targets

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Molecular glues are small molecules designed to stabilize or induce interactions between proteins.
  • Unlike PROTACs, molecular glues are typically smaller and possess favorable physicochemical properties.
  • They are frequently employed to enhance the interaction between a target protein and an E3 ligase.

Purpose of the Study:

  • To review the mechanism of induced proximity mediated by molecular glues.
  • To discuss current methodologies for identifying and screening molecular glues.
  • To introduce novel approaches applicable to molecular glue discovery.

Main Methods:

  • Literature review of molecular glue mechanisms and identification strategies.
  • Analysis of existing and emerging techniques for molecular glue screening.
  • Discussion of induced proximity principles in drug design.

Main Results:

  • Molecular glues can stabilize or induce protein-protein interactions, with common application in recruiting E3 ligases to target proteins.
  • Alternative applications include stabilizing beneficial interactions or inhibiting detrimental ones.
  • Various methods exist for molecular glue identification, with ongoing development in screening approaches.

Conclusions:

  • Molecular glues represent a promising modality for modulating protein interactions.
  • Understanding induced proximity is key to leveraging molecular glues effectively.
  • Further development of screening methods will accelerate the discovery of novel molecular glues.